VASH1/2 inhibition accelerates functional recovery of injured nerves

Abstract

Treatments accelerating axon regeneration in the nervous system are still unavailable in the clinic. However, in culture, parthenolide markedly promotes adult sensory neurons axon growth by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration, while the knockdown of vasohibins or their enhancer SVBP abolishes parthenolides effects, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-amino-parthenolide (DMAPT) markedly facilitates regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves and accelerates functional re-covery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT promising drugs for curing nerve injury.